Bi-aromatic compounds linked via a heteroethylene radical, and pharmaceutical and cosmetic compositions using them

ABSTRACT

Bi-aromatic compounds linked via a heteroethynylene radical are provided along with pharmaceutical and cosmetic compositions containing these compounds and methods for their use.

[0001] The present application is a continuation-in-part of applicationSer. No.09/768,496 filed Jan. 25, 2001, which is a divisional ofapplication Ser. No.09/267,977, filed Apr. 8, 1999 (now U.S. Pat. No.6,201,019, issued Mar. 13, 2001), which is a 371 U.S. national phase ofPCT/FR98/01835, filed Aug. 21, 1998 and claims benefit of FR-97 10554,filed Aug. 21, 1997.

[0002] The invention relates, as novel and useful industrial products,to bi-aromatic compounds whose aromatic rings are linked via a divalentheteroethynylene radical. The invention also relates to the use of thesenovel compounds in pharmaceutical compositions intended for use in humanor veterinary medicine, or alternatively in cosmetic compositions.

[0003] The compounds according to the invention have pronounced activityin the fields of cell differentiation and proliferation and findapplications more particularly in the topical and systemic treatment ofdermatological complaints associated with a keratinization disorder,dermatological (or other) complaints with an inflammatory and/orimmunoalergic component, and dermal or epidermal proliferations, whetherthey are benign or malignant. These compounds can also be used in thetreatment of connective tissue degenerative diseases, for combatingageing of the skin, whether this is light-induced or chronologicalageing, and for treating cicatrization disorders. They moreover find anapplication in the opthalmological field, in particular in the treatmentof corneopathy.

[0004] The compounds according to the invention can also be used incosmetic compositions for body and hair hygiene.

[0005] Bi-aromatic compounds whose aromatic rings are linked via adivalent propynylene have already been described in EP-661,258 as activesubstances in pharmaceutical or cosmetic compositions.

[0006] The compounds according to EP-661,258 correspond to the followinggeneral formula:

[0007] in which:

[0008] Ar is a divalent aromatic radical optionally substituted with aradical R₅ or a heteroaromatic radical optionally substituted with aradical R₆ when the hetero atom is nitrogen,

[0009] R₁ represents H, —CH₃, —CH₂OR₆, —OR₆, —COR₇ or —S(O)_(t)R₉, tbeing 0, 1 or 2.

[0010] R₂ and R₃ represent H, C₁-C₂₀ alkyl, —OR₆ or —SR₆,

[0011] or R₂ and R₃ taken together, form a 5- or 6-membered ringoptionally substituted with methyl groups and/or optionally interruptedby an oxygen or sulphur atom,

[0012] R₄ and R₅ represent H, a halogen, lower alkyl or —OR₆,

[0013] R₆ represents H, lower alkyl or —COR₉,

[0014] R₇ represents H, lower alkyl,

[0015]  or —OR₈,

[0016] R₈ represents H, linear or branched C₁-C₂₀ alkyl, alkenyl, mono-or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugaror amino acid or peptide residue,

[0017] R₉ represents lower alkyl,

[0018] R and R′ represent H, lower alkyl, mono- or polyhydroxyalkyl,optionally substituted aryl or a sugar, amino acid or peptide residue orR and R′, taken together, form a heterocycle, and

[0019] X represents a divalent radical which, from right to left orvice-versa, has the formula:

[0020] in which:

[0021] R₁₀ represents H, lower alkyl or —OR₆,

[0022] R₁₁ represents —OR₆,

[0023] or R₁₀ and R₁₁, taken together, form an oxo (═O) radical,

[0024] and the salts of the said compounds of the above formula when R₁represents a carboxylic acid function, and the optical and geometricalisomers of these said compounds.

[0025] The compounds according to the present invention differ fromthose of EP-661,258 essentially in that the radical X or divalentpropynylene radical has been replaced with a divalent heteroethynyleneradical.

[0026] The reason for this is that it has been found, surprisingly andunexpectedly, that this structural change makes it possible tosignificantly increase the pharmaceutical and cosmetic propertiesthereof and also to decrease certain side effects thereof.

[0027] A subject of the present invention is thus novel compounds whichcan be represented by the following general formula:

[0028] in which:

[0029] Ar represents a radical chosen from the formulae (a) to (c)below:

[0030] Z being O or S, or N—R₆,

[0031] R₁ represents a halogen atom, —CH₃, —CH₂—OR₇, —OR₇, —COR₈ or apolyether radical,

[0032] R₂ and R₃, which may be identical or different, represent H,linear or branched C₁-C₂₀ alkyl, C₃-C₁₂ cycloalkyl, —OR₇ or —SR₇, atleast one from among R₂ and R₃ being linear or branched C₁-C₂₀ alkyl orC₃-C₁₀ cycloalkyl, or

[0033] R₂ and R₃, taken together, form a 5- or 6-membered ring,optionally substituted with at least one methyl and/or optionallyinterrupted by a hetero atom chosen from O and S, p1 R₄ and R₅ representH, a halogen atom, linear or branched C₁-C₂₀ alkyl, —OR₇ or a polyetherradical,

[0034] R₆ represents H, linear or branched C₁-C₁₀ alkyl or —OCOR₉,

[0035] R₇ represents H, linear or branched C₁-C₁₀ alkyl or —COR₉,

[0036] R₈ represents H, linear or branched C₁-C₁₀, alkyl, —OR₁₀ or

[0037] R₉ represents linear or branched C₁-C₁₀ alkyl,

[0038] R₁₀ represents H, linear or branched C₁-C₂₀ alkyl, mono- orpolyhydroxvalkyl, allyl, optionally substituted aryl or aralkyl, or asugar residue,

[0039] r′ and r″, which may be identical or different, represent H,C₁-C₁₀ alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, anamino acid or peptide residue, or, taken together with the nitrogenatom, form a heterocycle,

[0040] X represents a divalent radical which, from right to left orvice-versa, has the formula:

[0041] in which:

[0042] Y represents O, S(O)_(n) or Se(O)_(n′),

[0043] n and n′ being 0, 1 or 2,

[0044] with the proviso that when n=2 and Ar is a radical of formula (a)above, in which R₁=—CH₃ and R₅=H, then at least one of the radicals R₂or R₃ is other than —CH₃,

[0045] and the salts of the compounds of formula (I) when R₁ representsa carboxylic acid function, as well as the optical isomers of the saidcompounds of formula (I).

[0046] When the compounds according to the invention are in the form ofa salt, this is preferably a salt of an alkali metal or alkaline-earthmetal, or alternatively of zinc or of an organic amine.

[0047] According to the present invention, the term “C₁-C₁₀ alkyl”preferably refers to the methyl, ethyl, isopropyl, butyl, tert-butyl,hexyl, 2-ethylhexyl and octyl radicals.

[0048] The term “linear or branched C₁-C₂₀ alkyl” refers in particularto the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyland octadecyl radicals.

[0049] The term “C₃-C₁₂ cycloalkyl radical” refers to a mono- orpolycyclic radical, in particular the cyclopropyl, cyclopentyl,cyclohexyl, 1-methylcyclo-hexyl and 1-adamantyl radicals.

[0050] The term “polyether radical” refers to a radical containing from2 to 5 carbon atoms interrupted by at least two oxygen atoms, such asthe methyloxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.

[0051] The term “monohydroxyalkyl” refers to a radical preferablycontaining 2 or 3 carbon atoms, in particular a 2-hydroxyethyl,2-hydroxypropyl or 3-hydroxypropyl radical.

[0052] The term “polyhydroxyalkyl” refers to a radical preferablycontaining 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such asthe 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.

[0053] The term “aryl” preferably refers to a phenyl radical optionallysubstituted with at least one halogen atom, a hydroxyl or a nitrofunction.

[0054] The term “aralkylo” preferably refers to a benzyl or phenethylradical optionally substituted with at least one halogen atom, ahydroxyl or a nitro function.

[0055] The term “sugar residue” refers to a residue derived inparticular from glucose, from galactose or from mannose, oralternatively from glucuronic acid.

[0056] The term “amino acid residues” refers in particular to a residuederived from lysine, from glycine or from aspartic acid, and the term“peptide residue” refers more particularly to a dipeptide or tripeptideresidue resulting from the combination of amino acids.

[0057] The term “heterocycle” preferably refers to a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted inposition 4 with a C₁-C₆ lower alkyl or a mono- or polyhydroxyalkyl asdefined above.

[0058] When R₁, R₄ and/or R₅ represents a halogen atom, this ispreferably a fluorine, chlorine or bromine atom.

[0059] According to a first preferred embodiment, the compoundsaccording to the invention correspond to the following general formula:

[0060] in which:

[0061] Ar′ represents a radical of formula:

[0062] R₁, R₄, R₅ and X being as defined above for formula (I),

[0063] R₁₁, R₁₂, R₁₃ and R₁₄, which may be identical or different,represent H or —CH₃, and

[0064] n is 1 or 2.

[0065] According to a second preferred embodiment, the compoundsaccording to the invention correspond to the following formula:

[0066] in which:

[0067] W represents O or S,

[0068] R₄, R₁₁, R₁₂, Ar′ and X being as defined above in the formulae(I) and (II).

[0069] Lastly, according to a third preferred embodiment, the compoundsaccording to the invention correspond to the following formula:

[0070] in which:

[0071] R₄, Ar′ and X are as defined above in formulae (I) to (III), and

[0072] at least one of the radicals R′₂ and/or R′₃ represents a mono- orpolycyclic C₅-C₁₀ cycloalkyl radical, the other representing one of themeanings given for R₂ or R₃.

[0073] Among the compounds of formulae (I) to (IV) above, according tothe present invention, mention may be made in particular of thefollowing:

[0074] Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,

[0075]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylehynyl)benzoicacid,

[0076] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,

[0077] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoate,

[0078]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoicacid,

[0079] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,

[0080]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid,

[0081] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,

[0082]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoicacid,

[0083] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoate,

[0084]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoicacid,

[0085] Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0086]4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0087] Methyl2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0088]2-Hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0089]6-(4-methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,

[0090] Ethyl6-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,

[0091]6-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,

[0092]N-(4-Hydroxyphenyl)-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide,

[0093] Methyl5-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridimecarboxylate,

[0094]2-(4-Chlorophenylselanylethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,

[0095] Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0096]4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzaicacid,

[0097] Methyl2-hydroxy-4-(3,5,5,8,8-pentamethlyl-5,6,7,8-tetahydro-2-naphthylselanylethynyl)benzoate,

[0098]2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0099] Ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,

[0100]6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,

[0101]N-(4-Hydroxyphenyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,

[0102]N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,

[0103]Morpholin-4-yl-[6-(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone,

[0104] Methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napathylselanylethynyl)pyridine-2-carboxylate,

[0105]5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2naphthylselanylethynyl)pyridine-2-carboxylicacid,

[0106][4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol,

[0107] Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate,

[0108] Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoate,

[0109] Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoate,

[0110]4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoicacid,

[0111]4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoicacid,

[0112]4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoicacid,

[0113]4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol,

[0114] Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0115] Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0116]4-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0117]4-(4-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0118] Ethyl4-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0119] Ethyl4-(3-methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0120]4-(3-Methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0121]4-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0122] Ethyl4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

[0123]4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[0124][4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde,

[0125] Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynyl)benzoate,

[0126] 4-(4,4-Dimethylthiochroman-8-ylselanylethynyl)benzoic acid,

[0127] Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoate,

[0128]4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoicacid,

[0129] Methyl4-[3-(1-adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoate,

[0130] 4-[3-(1-Adamantyl)-4-methoxyphenyl))-1-ylselanylethynyl]benzoicacid,

[0131] Methyl4-[4-(1-adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoate, and

[0132] 4-[4-(1-Adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoicacid.

[0133] A subject of the present invention is also the processes forpreparing the compounds of formula (I) above according to the reactionschemes given in Tables A and B.

[0134] With reference to Table A, the compounds of formula (I) in whichX represents the divalent radical

[0135] i.e. the compounds of formula (Ia), can be obtained according totwo different synthetic routes depending on whether Y=oxygen orY≠oxygen.

[0136] When X=oxygen, the starting material is the compound of formula(1), which, in the presence of a base such as potassium hydride orsodium hydride, is then coupled with trichloroethylene. Thedichloroethylene product obtained, of formula (2), is then subjected tothe action of a lithiated base, such as butyllithium, in a solvent suchas THF, to give the acetylenic compound of formula (3). This acetyleneis then coupled with an aryl halide or a heteroaryl halide, preferablyan iodo derivative, in the presence of a palladium catalyst to give thecompounds of formula (IIa) with Y=oxygen.

[0137] When Y≠oxygen, the lithium acetylide of formula (5) is firstprepared, from the aromatic or heteroaromatic acetylenic compound (4),in the presence of a lithiated derivative such as butyllithium, in asolvent such as THF. Starting with the lithium acetylide (5), which isnot isolated, a coupling is carried out with the compound of formula(6), in a solvent such as THF, to give the compounds of formula (Ia)with Y≠oxygen.

[0138] Starting with these compounds of formula (Ia) in which Y═S or Se,it is possible to gain access to the oxidized derivatives by oxidationusing an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) orsodium periodate.

[0139] With reference now to Table B, the compounds of formula (I), inwhich X represents a divalent radical

[0140] i.e. the compounds of formula (Ic), can also be obtainedaccording to two different synthetic routes depending an whetherY=oxygen or Y≠oxygen.

[0141] When Y=oxygen, the starting material is an aromatic orheteroaromatic compound of formula (7), which, in the presence of a basesuch as potassium hydride or sodium hydride, in a solvent such as THF,is then coupled with trichloroethylene. The dichloro-ethylene productobtained (8) is then subjected to the action of a lithiated base such asbutyllithium, in THF, to give the oxoacetylenic compound of formula (9).This acetylene is then coupled with an aryl halide (10), preferably aniodo derivative, in the presence of a palladium catalyst, to give thecompounds of formula (Ic) with Y=oxygen.

[0142] When Y≠oxygen; the starting material is an aromatic acetyleniccompound of formula (11), which is converted into a lithiated derivativein the presence of butyllithium, for example in a solvent such as THF.The lithiated acetylenic derivative (12), which is not isolated, is thencoupled with an aromatic or heteroaromatic compound of formula (13), thecoupling reaction being carried out in a solvent such as THF. Thecompounds of formula (Ic) with Y≠oxygen are thus obtained by thissynthetic route.

[0143] Starting with these compounds of formula (Ic), in which Y═S orSe, it is also possible to obtain the oxidized derivatives by oxidationusing an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) orsodium periodate.

[0144] When, in the compounds according to the invention, the radical R₁represents —COOH, these radicals are prepared by protecting thecarboxylic acid function with a protecting group or the alkyl type.

[0145] By saponification of ester function in the presence of a basesuch as sodium hydroxide or lithium hydroxide in an alcoholic solvent orin THF, the corresponding free acids are thus obtained.

[0146] When R₁ is —OH, the compounds can be obtained from thecorresponding acid by reduction in the presence of hydride such as boronhydride.

[0147] When R₁ is —CH═O, the compounds can be obtained by oxidation ofthe corresponding alcohols using manganese oxide or pyridiniumdichromate.

[0148] When R₁ is

[0149] the compounds can be obtained by conversion of the correspondingacid into the acid chloride, for example with thionyl chloride, followedby reaction with aqueous ammonia or a suitable amine.

[0150] A subject of the present invention is also the compounds offormula (I) as defined above, as medicinal products.

[0151] The compounds of general formula (I) have agonist or antagonistactivity with respect to the expression of one or more biologicalmarkers in the test of differentiation of mouse embryonicteratocarcinoma cells (F9) (Skin Pharmacol. 3, p. 256-267, 1990) and/oron the in vitro differentiation of human keratinocytes (Skin Pharmacol.3, p. 70-85, 1990). These abovementioned tests show the activities ofthe compounds in the fields of differentiation and proliferation. Theactivities can also be measured in cellular transactivation tests usingRAR recombinant receptors according to the method by B. A. Bernard etal., Biochemical and Biophysical Research Communication, vol. 186,977-983, 1992.

[0152] The compounds according to the invention are particularlysuitable in the following fields of treatment:

[0153] 1) for treating dermatological complaints associated with akeratinization disorder which has a bearing on differentiation and onproliferation, in particular for treating common acne, comedones,polymorphonuclear leukocytes, rosacea, nodulocystic acne, acneconglobata, senile acne and secondary acne such as solar,medication-related or occupational acne,

[0154] 2 ) for treating other types of keratinization disorder, inparticular ichthyosis, ichthyosiform states, Darier's disease,palmoplantar keratoderma, leucoplasias and leucoplasiform states, andcutaneous or mucous (buccal) lichen,

[0155] 3) for treating other dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent and, in particular, all forms of psoriasis, whether it iscutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds can also be used incertain inflammatory complaints which have no keratinization disorder;

[0156] 4) for treating all dermal or epidermal proliferations, whetherbenign or malignant and whether they are of viral origin or otherwise,such as common warts, flat warts and verruciform epidermodysplasia, itbeing also possible for the oral or florid papillomatoses and theproliferations to be induced by ultraviolet radiation, in particular inthe case of basocellular and spinocellular epithelioma,

[0157] 5) for treating other dermatological disorders such as bullosisand collagen diseases,

[0158] 6) for treating certain ophthalmological disorders, in particularcorneopathies,

[0159] 7) for repairing or combating ageing of the skin, whether this islight-induced or chronological ageing, or for reducing actinic keratosesand pigmentations, or any pathologies associated with chronological oractinic ageing,

[0160] 8) for preventing or curing the stigmata of epidermal and/ordermal atrophy induced by local or systemic corticosteroids, or anyother form of cutaneous atrophy,

[0161] 9) for preventing or treating cicatrization disorders or forpreventing or repairing stretch marks,

[0162] 10) for combating disorders of sebaceous functioning such as thehyperseborrhoea of acne or simple seborrhoea,

[0163] 11) in the treatment or prevention of cancerous or precancerousstates,

[0164] 12) in the treatment of inflammatory complaints such asarthritis,

[0165] 13) in the treatment of any general or skin complaint of viralorigin,

[0166] 14) in the prevention or treatment or alopecia,

[0167] 15) in the treatment of dermatological or general complaintshaving an immunological component, and 16) in the treatment ofcomplaints of the cardiovascular system such as arteriosclerosis

[0168] In the therapeutic fields mentioned above, the compoundsaccording to the invention mar be employed advantageously in combinationwith other compounds of retinoid-type activity, with D vitamins orderivatives thereof, with corticosteroids, with anti-free-radicalagents, α-hydroxy or α-keto acids or derivatives thereof, oralternatively with ion-channel blockers. The expression “D vitamins orderivatives thereof” means, for example, vitamin D₂ or D₃ derivativesand in particular 1,25-dihydroxyvitamin D₃. The expression“anti-free-radical agents” means, for example, α-tocopherol, superoxidedismutase or SOD, ubiquinol or certain metal-chelating agents. Theexpression “α-hydroxy or α-keto acids or derivatives thereof” means, forexample, lactic, malic, citric, glycolic, mandelic, tartaric, glycericor ascorbic acid or the salts, amides or esters thereof. Lastly, theterm “ion-channel blockers” means, for example, Minoxidil(2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereon.

[0169] A subject of the present invention is also pharmaceuticalcompositions containing at least one compound of formula (I) as definedabove, one of the optical or geometrical isomers thereof or one of thesalts thereof.

[0170] The pharmaceutical compositions are intended in particular fortreating the abovementioned complaints, and are characterized in thatthey comprise a pharmaceutically acceptable support which is compatiblewith the mode of administration selected, at least one compound offormula (I), one of the optical or geometrical isomers thereof or one ofthe salts thereof.

[0171] The compounds according to the invention may be administeredenterally, parenterally, topically or ocularly.

[0172] Via the enteral route, the compositions may be in the form oftablets, gelatin capsules, sugar-coated tablets, syrups, suspensions,solutions, powders, granules, emulsions, microspheres or nanospheres orpolymeric or lipid vesicles which enable controlled release. Via theparenteral route, the compositions may be in the form of solutions orsuspensions for infusion or for injection.

[0173] The compounds according to the invention are generallyadministered at a daily dose of about 0.01 mg/kg to 100 mg/kg of bodyweight taken in 1 to 3 doses.

[0174] Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucosae and may then be in the form ofointments, creams, milks, salves, powders, impregnated pads, solutions,gels, sprays, lotions or suspensions. They may also be in the form ofmicrospheres or nanospheres or polymeric or lipid vesicles or polymericpatches and hydrogels which enable controlled release of the activeprinciple. Furthermore, these topical-route compositions may either bein anhydrous form or in aqueous form, depending on the clinicalindication.

[0175] Via the ocular route, they are mainly eyedrops.

[0176] These compositions for topical or ocular use contain at least onecompound of formula (I) as defined above, or one of the optical orgeometrical isomers thereof or alternatively one of the salts thereof,at a concentration preferably of between 0.001% and 5% by weightrelative to the total weight of the composition.

[0177] The compounds of formula (I) according to the invention also findan application in the cosmetic field, in particular in body and hairhygiene and especially for treating skin types with a tendency towardsacne, for promoting the regrowth of the hair, for combating hair loss,for combating the greasy appearance of the skin or the hair, inprotection against the harmful effects of the sun or in the treatment ofphysiologically dry skin types, and for preventing and/or combatinglight-induced or chronological ageing.

[0178] In the cosmetic field, the compounds according to the inventioncan moreover be employed advantageously in combination with othercompounds of retinoid-type activity, with D vitamins or derivativesthereof, with corticosteroids, with anti-free-radical agents, α-hydroxyor α-keto acids or derivatives thereof, or alternatively withion-channel blockers, all or these latter compounds being as definedabove.

[0179] The present invention is thus also directed towards a cosmeticcomposition which is characterized in that it comprises, in acosmetically acceptable support, at least one compound of formula (I) asdefined above or one of the optical or geometrical isomers thereof orone of the salts thereof, it being possible for the said cosmeticcomposition to be, in particular, in the form or a cream, a milk, alotion, a gel, microspheres or nanospheres or polymeric or lipidvesicles, a soap or a shampoo.

[0180] The concentration of compound of formula (I) in the cosmeticcompositions according to the invention is advantageously between 0.001%and 3% by weight relative to the total weight of the composition.

[0181] The pharmaceutical and cosmetic compositions according to theinvention can also contain inert additives or even pharmacodynamicallyor cosmetically active additives or combinations of these additives and,in particular: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; moisturizingagents such as glycerol, PEG-400, thiomorpholino and derivativesthereof, or urea; anti-seborrhoea or anti-acne agents such asS-carboxymethylcysteine, S-benzylcysteamine, the salts or derivativesthereof, or benzoyl peroxide; antibiotics such as erythromycin andesters thereof, neomycin, clindamycin and esters thereof, andtetracyclines; antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowthof the hair, such as Minoxidil(2,4-diamino-6-piperidinocyrimidine-3-oxide) and derivatives thereof,Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andPhenytoin (5,4-diphenyl-imidazolidine-2,4-dione); non-steroidalanti-inflammatory agents; carotenoids and, in particular, β-carotene;anti-psoriatic agents such as anthraline and derivatives thereof and,lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoicacid, the esters and amides thereof.

[0182] The compositions according to the invention may also containflavour-enhancing agents, preserving agents such as para-hydroxybenzoicacid esters, stabilizing agents, moisture regulators, pH regulators,osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screeningagents, and antioxidants such as α-tocopherol, butylated hydroxyanisoleor butylated hydroxytoluene.

[0183] Several examples for obtaining the active compounds of formula(I) according to the invention, as well as various cosmetic andpharmaceutical formulations based on such compounds, will now be givenfor illustrative purposes and with no limiting nature.

EXAMPLES Example 1

[0184] Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-nachthylsuphanylethynyl)-benzoate

[0185] (a) Methyl 4-trimethylsilylethynylbenzoate

[0186] 21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml oftriethylamine and a mixture of 200 mg of palladium acetate and 400 mg oftriphenylphosphine are introduced into a three-necked flask. 20 g (0.204mol) of trimethylsilylacetylene are then added, after which the mixtureis heated gradually to 90° C. over 1 hour and left at this temperaturefor 5 hours. The reaction medium is then cooled, the salt is filtered ofand the filtrate is evaporated. The residue is taken up in 200 ml ofhydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase isseparated out after settling has taken place, washed with water, driedover magnesium sulphate and evaporated. The residue obtained is purifiedby chromatography on a column of silica eluted with dichloromethane.After evaporation of the solvents, 23 g (100%) of the expectedderivative are collected in the form of a colourless oil.

[0187] (b) Methyl 4-ethynylbenzoate

[0188] 38.33 g (226 mmol) of the product obtained above in 300 ml ofmethanol are introduced into a three-necked flask. 125 g of potassiumcarbonate are then added and the medium is stirred for 48 hours at roomtemperature. The solvent is evaporated off and the residue obtained ispurified by chromatography on a column of silica eluted withdichloromethane. After evaporation of the solvents, the residue is takenup in heptane and, after filtration, 32 g (100%) of the expectedderivative are collected in the form of a straw-yellow solid.

[0189] (c) Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate

[0190] A 2.5 M solution of butyllithium in hexane (20 mmol, 8.1 ml) isadded to a solution of methyl 4-ethynylbenzoate (3 g, 18.7 mmol) in THF(300 ml) at −78° C. The temperature is maintained for 45 minutes and isthen raised to −40° C. A solution of5,6,7,8-tetrahydro-5,5,3,8-tetramethyl-2-naphthalene disulphide (J. Med.Chem. 1995, 38, 3171) (16.5 g, 37.4 mmol) in THF (60 ml) is then addedat this temperature. The reaction medium is then stirred for 1 hour at0° C., after which it is poured into a mixture of ethyl ether andsaturated ammonium chloride solution. The organic phase is washed twicewith water, dried over anhydrous magnesium sulphate and concentrated ona rotary evaporator under vacuum at 40° C. After chromatography on acolumn of silica, using a mixture of heptane/methylene chloride (60/40),and after evaporation, 1.9 g of a white solid (27%) are obtained.

[0191]¹H (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92 (3H,s), 7.25 to 7.31 (2H Ar, m), 7.42 (1H Ar, d, J=2 Hz), 7.50 (1H, Ar, d,J=7.5 Hz), 8.00 (1H, Ar, d, J=7.5 Hz).

[0192] 13_(c) (CDCl₃): 32.25 (CH3), 34.60 (C), 35.02 (C), 35.36 (CH₂),52.68 (OCH₃), 81.26 (C), 96.96 (C), 124.82 (CH Ar), 125.56 (CH Ar),128.29 (C Ar), 128.37 (CH Ar), 128.85 (C Ar), 129.88 (C Ar), 130.04 (2CH Ar), 131.29 (2 CH Ar), 144.66 (C, Ar), 146.88 (C Ar), 166.95 (COO).

Example 24-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsuphanylethynyl)benzoicacid

[0193] A solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate (590 mg, 1.6 mmol) and oflithium hydroxide (383 mg, 9.3 mmol) in THF is refluxed for 24 hours.The reaction mixture is poured into an Et₂O/water mixture, acidified topH 1 with concentrated hydrochloric acid solution, and extracted oncewith ethyl ether. After separation of the phases by settling, theorganic phase is washed twice with water, dried over magnesium sulphateand concentrated on a rotary evaporator under vacuum at 40° C. The solidobtained is crystallized from heptane and 440 mg (77%) of a white solidare obtained. m.p. (melting point)=193.50° C.

[0194] NMR δ ppm:

[0195]¹H (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 7.29 to 7.32(2H Ar, m), 7.42 (1H Ar, d, J=2 Hz), 7.53 (1H Ar, d, J=8, 5 Hz), 8.08(1H Ar, d, J=8.5 Hz).

[0196] 13_(c) (CDCl₃): 31.44 (CH₃), 33.80 (C), 34.22 (C), 34.54 (CH₂),81.30 (C), 100.01 (C), 124.06 (CH Ar), 124.81 (CH Ar), 127.59 (CH Ar),127.94 (C Ar), 128.46 (C Ar), 129.87 (2 CH Ar), 130.49 (2 CH Ar), 143.93(C Ar), 146.12 (C Ar), 171.06 (COO).

Example 3 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsuphonylethynyl)benzoate

[0197] A solution of meta-perbenzoic acid (700 mg) in CHCl₃ (12 ml) isadded dropwise, at 0° C., to a solution of the product of Example 1 (500mg, 1.3 mmol) in 6 ml of CHCl₃. After stirring for 1 hour, the mixtureis concentrated on a rotary evaporator under vacuum. Afterchromatography on a column of silica with a heptane/methylene chloridemixture (30/70), 280 mg of a white solid are obtained (52%).

[0198]¹H (CDCl₃): 1.32 (6H, s), 1.34 (6H, s), 1.73 (4H, s), 3.93 (3H,s), 7.51 (2H Ar, d, J=8.3 Hz), 7.60 (2H Ar, d, J=8.5 Hz), 7.78 (1H Ar,dd, J1=8.5 Hz, J2=2 Hz) , 7.98 to 8.05 (3H Ar, m).

[0199] 13_(c) (CDCl₃) : 31.63 (CH₃), 31.73 (CH₃), 34.58 (CH₂), 34.64(CH₂), 34.85 (C), 34.98 (C), 52.52 (CH₃), 87.77 (C), 90.99 (C), 122.61(C Ar), 124.35 (CH Ar), 125.99 (CH Ar), 128.04 (CH Ar), 129.68 (CH Ar),132.44 (C Ar), 132.69 (CH Ar), 138.37 (C Ar), 152.50 (C Ar), 165.83(COO).

Example 4 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0200] (a) 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenediselenide

[0201] A 1.7 M solution of tert-butyllithium in pentane (37.4 mmol, 22ml) is added to a solution of2-bromo-5,6,7,8-tetrahydro-5,5,8,8-teramethyl-naphthalene (4.22 g, 15.8mmol) in THF (100 ml) at −78° C. over 10 min. The mixture is stirred at0° C. for 30 min. Selenium (1.33 g, 16.8 mmol) is added in two portions.The mixture is stirred at 0° C. for 15 min and then at room temperaturefor 30 min. 1N HCl solution (40 ml) is added and the reaction mixture isthen treated with ethyl ether. The organic phase is washed twice withwater, dried over anhydrous magnesium sulphate and concentrated on arotary evaporator under vacuum at 40° C. 10 ml of ethanol and 50 mg ofsodium hydroxide are added to the oil obtained. The mixture is stirredvigorously for a few minutes and is then concentrated on a rotaryevaporator under vacuum at 40° C. The solid obtained is filtered throughsilica (eluted with heptane) and then crystallized from an ethanol/ethermixture. After filtration, 2.9 g (69%) of an orange-coloured solid areobtained.

[0202]¹H NMR (CDCl₃): 1.21 (6H, s), 1.25 (6H, s), 1.65 (4H, s), 7.20 (1HAr, d, J=8.25 Hz), 7.38 (1H Ar, dd, J=1.9 Hz, J=8.25 Hz), 7.51 (1H Ar,d, J=1.9 Hz).

[0203] (b) Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0204] Bromine (0.15 ml, 2.9 mmol) is added to a solution of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene diselenide (1.5 g,2.8 mmol) in THF (3 ml). The mixture is stirred at room temperature for2 h and the solvent is then removed. Copper iodide (2.15 g, 11.3 mmol),methyl 4-ethynylbenzoate (810 mg, 5 mmol) obtained according to Example1(b) and DMF (15 ml) are added. The reaction mixture is stirred at roomtemperature for 3 h and is then treated with ethyl ether and aqueousammonia solution. The organic phase is washed twice with water, driedover anhydrous magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. The residue is recrystallized fromheptane and, after filtration, 1.8 g (75%) of a white powder areobtained. m.p.=90-1° C.

[0205]¹H NMR (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92(3H, s), 7.29 (1H Ar, d, J=8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8.3Hz), 7.48 to 7.53 (3H Ar, m), 7.98 (2H Ar, d, J=8.5 Hz).

Example 54-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

[0206] Lithium hydroxide (440 mg) is added to a solution of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(740 mg, 1.74 mmol), obtained in Example 4, in 15 ml of THF and 2 ml ofa water/methanol mixture (1/1). The reaction medium is refluxed for 8 h.It is then poured into an ethyl ether/water mixture, acidified to pH 1with concentrated hydrochloric acid solution and extracted with ethylether. After separation of the phases by settling, the organic phase iswashed twice with water, dried over anhydrous magnesium sulphate andconcentrated on a rotary evaporator under vacuum at 40° C. The residueis recrystallized from heptane. After filtration, 615 mg (86%) of awhite powder are obtained. m.p.=182° C.

[0207]¹H NMR (CDCl₃): 1.28 (6H, s), 1.30 (6H, s) , 1.69 (4H, s), 7.29(1H Ar, d, J=8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz), 7.52 to 7.55(3H Ar, m), 8.07 (2H Ar, d, J=8.5 Hz).

Example 6 Methyl2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0208] (a) Methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate

[0209] In a manner similar to that of Example 1(a), starting with 4.00 g(14.4 mmol) of methyl 4-iodo-2-hydroxybenzoate, 3.07 g (86%) of theexpected compound are obtained in the form of an orange-coloured oil.

[0210]¹H NMR (CDCl₃): 0.06 (s, 9H), 3.75 (s, 3H), 6.76 (dd, 1H,J=8.2/1.5 Hz), 6.87 (d, 1H, J=1.4 Hz), 7.56 (d, 1H, J=8.2 Hz), 10.53 (s,1H).

[0211] (b) Methyl 4-ethynyl-2-hydroxybenzoate

[0212] 3.07 g (12.4 mmol) of methyl4-trimethylsilanylethynyl-2-hydroxybenzoate are mixed, in a 500 mlthree-necked flask, with 50 ml of THF, and 13.7 ml of atetrabutylammonium fluoride solution (1 M/THF) are added dropwise. Thereaction medium is stirred for 1 h at room temperature and is thenpoured into water and extracted with ethyl ether. After separation ofthe phases by settling, the organic phase is dried over magnesiumsulphate and concentrated. 2.48 g (100%) of a beige-coloured powder areobtained. m.p.=62° C.

[0213]¹H NMR (CDCl₃): 3.21 (s, 1H), 3.96 (s, 3H), 6.98 (dd, 1H,J=8.2/1.5 Hz), 7.10 (d, 1H, J=1.3 Hz), 7.78 (d, 1H, J=8.2 Hz), 10.76 (s,1H).

[0214] (c) Methyl2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0215] In a manner similar to that of Example 4(b), after reaction of1.5 g (2.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenediselenide, in 2 ml of THF, with bromine (0.15 ml, 2.9 mmol), copperiodide (2.15 g; 11.3 mmol) and methyl 4-ethynyl-2-hydroxybenzoate (890mg; 5 mmol) in 10 ml of DMF are added. After purification on a column ofsilica (dichloromethane 10/heptane 90), 2.15 g (97%) of the expectedester derivative are obtained in the form of a yellow solid. m.p.=70° C.

[0216]¹H NMR (CDCl₃): 1.28(d,12H); 1.69(s,4H); 3.95(s,3H); 6.94(dd,1H);7.04(d,1H); 7.26 to 7.37(m,2H); 7.51(d,1H); 7.77(d,1H); 10.77(s,1H).

[0217]¹³C NMR (CDCl₃): 31.8; 4CH3/34.2; Cq/34.6; Cq/34.9; 2CH2/52.4;CH3/75.1; Cq/101.6; Cq/111.9; Cq/119.7; CH/121.9; CH/124.5; Cq/127.0;CH/127.8; CH/128.1; CH/129.9; CH/130.4; Cq/144.7; C/146.7; Cq/161.2;Cq/170.1; Cq.

Example 72-Hydroxy-4-(5,5,8,8-tetramethyl)-5,6,7,8-tetrahydro-2-nauhthylselanylethynyl)benzoicacid

[0218] A solution of2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(1.2 g; 2.72 mmol) obtained in Example 6(c) and sodium hydroxide (1.5 g;37.5 mmol) in 20 ml of THF is refluxed for 24 h. The reaction medium isthen poured into an ethyl acetate/water mixture, acidified to pH 1 withconcentrated hydrochloric acid solution and extracted once with ethylacetate. After separation of the phases by settling, the organic phaseis washed twice with water, dried over magnesium sulphate andconcentrated on a rotary evaporator under vacuum at 40° C. 1 g (86%) ofa yellow solid is obtained. m.p.=170° C.

[0219]¹HNR (DMSO): 1.28(m,12H); 1.68(s,4H); 6.95(d,1H); 7.03(s,1H); 7.25to 7.37(m,2H); 7.51(s,1H); 7.83(d,1H).

[0220]¹³C NMR (DMSO): 31.8; 4CH3/34.2; Cq/34.6; Cq/34.9; 2CH2/76.0;Cq/101.5; Cq/119.7; CH/122.1; CH/124.4; Cq/127.1; Cq/127.9; CH/128.2;CH/130.9; CH/131.4; Cq/144.7; Cq/146.7; Cq/161.6; Cq/174.2; Cq.

Example 86-(4-Methoxymethoyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene

[0221] (a) 1-Iodo-4-methoxymethoxybenzene

[0222] 5 g (22.7 mmol) of 4-iodophenol are added to a suspension or 75%sodium hydride (872 mg; 27.25 mmol) in 20 ml of dimethylformamide. Themixture is stirred for 30 minutes at room temperature and 2.59 ml (34.1mmol) of methoxymethyl chloride are then added. The solution is stirredfor 2 h and the medium is then poured into an ethylacetate/watermixture. After separation of the phases by settling, the organic phaseis washed twice with water, dried over magnesium sulphate andconcentrated on a rotary evaporator under vacuum at 40° C. 5.74 g (96%)of a colourless oil are obtained.

[0223]¹H NMR (CDCl₃): 3.45(s,3H); 5.13(s,2H); 6.80(d, 2H); 7.55(d,2H)

[0224]¹³C NMR (CDCl₃): 56.0; CH3/84.3; Cq/94.3; CH2/118.4; 2CH/138.2;2CH/157.0; Cq

[0225] (b) 1-Trimethylsilylethynyl-4-methoxymethoxybenzene

[0226] 5.74 g (21.7 mmol) of 1-iodo-4-methoxymethoxybenzene, 100 ml ortriethylamine and a mixture of 1.53 g (2.18 mmol) ofdichloro-bis(triphenylphosphine)palladium and 831 mg (4.37 mmol) ofcopper iodide are introduced into a three-necked flask. 6.14 ml (43.5mmol) of trimethylsilylacetylene are then added and the medium isstirred for 48 h at room temperature. It is then poured into awater/ethyl acetate mixture. The organic phase is washed twice withwater and, after separation of the phases by settling, it is washed withmagnesium sulphate and concentrated.

[0227] (c) 1-Ethynyl-4-methoxymethoxybenzene

[0228] In a manner similar to that of Example 1(b), by reaction of theproduct obtained according to Example 8(b) with 50 ml of methanol andwith potassium carbonate for 15 h at room temperatures and afterpurification on a column of silica (dichloromethane 20/heptane 80), 840mg (24%) of the expected product are obtained in the form of a yellowoil.

[0229]¹H NMR (CDCl₃)): 3.00(s,1H); 3.46(s,3H); 5.17(s,2H); 6.97(d, 2H);7.42(d,2H).

[0230]¹³C NMR (CDCl₃): 56.1; CH3/76.1; Cq/83.5; CH/94.2; CH2/115.4;Cq/116.1; CH/133.6; CH/157.6; Cq

[0231] (d)6-(4-Methoxymethoxyphenylethynylselanyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene

[0232] In a manner similar to that of Example 4(b), after reaction of1.3 g (2.44 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene diselenide, in 2 mlof THF, with bromine (0.13 ml, 2.5 mmol), copper iodide (1.86 g; 9.8mmol) and 1-ethynyl-4-methoxymethoxybenzene (713 mg; 4,4 mmol) in 10 mlof DMF are added. After purification on a column of silica(dichloromethane 20/heptane 80), 1.7 g (90%) of the expected derivativeare obtained in the form of a yellow oil.

[0233]¹H NMR (CDCl₃): 127(m,12H); 1.67(s,4H); 3.47(s,3H); 5.18(s,2H);6.98(dd,2H); 7.01 to 7.51(m,5H).

[0234]¹³C NMR (CDCl₃): 31.8; 4CH3/34.1; Cq/34.5; Cq 34.9; 2CH2/56.1;CH3/68.3; Cq/77.5; Cq/102.0; Cq/116.1; 2Ch/116.7; Cq/125.3; Cq/133.3;2CH/144.2; Cq/146.5; Cq/157.4; Cq.

Example 96-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid

[0235] (a) Ethyl 6-trimethylsilylethynyl-3-pyridine-carboxylate

[0236] In a manner similar to that of Example 1(a), starting with 4 g(14.4 mmol) of methyl 6-iodo-3-pyridinecarboxylate, 3.29 g (92%) of theexpected compound are obtained in the form of a beige-coloured powder.m.p.=55° C.

[0237]¹H NMR (CDCl₃) δ0.10 (s, 9H), 1.22 (t, 2H, J=7.1 Hz), 4.23 (q, 3H,J=7.1 Hz), 7.33 (d, 1H, J=8.2 Hz), 8.06 (dd, 1H, J=8.1/2.1 Hz), 8.97 (d,1H, J=2.1 Hz).

[0238] (b) Ethyl 6-ethynylnicotinate

[0239] In a manner similar to that of Example 6(b), starting with 3.29 g(13.3 mmol) of ethyl 6-trimethylsilylethynylnicotinate, 1.00 g (43%) ofthe expected compound is obtained in the form of beige-coloured flakes.m.p.=35° C.

[0240]¹H NMR (CDCl₃) δ1.42 (t, 3H, J=7.1 Hz), 3.33 (s, 1H), 4.42 (q, 2H,J=7.2 Hz), 7.56 (d, 1H, J=8.1 Hz), 8.28 (dd, 1H, J=8.1/2.1 Hz), 9.18 (d,1H, J=2.0 Hz)

[0241] (c) Ethyl6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate

[0242] In a manner similar to that of Example 4(b), after reaction of1.84 g (3.4 mmol) of5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalene diselenide, in 2ml of THF, with bromine (0.18 ml, 3.49 mmol), copper iodide (2.64 g;13.9 mmol) and ethyl 6-ethynylnicotinate (1 g; 5.7 mmol) in 10 ml of DMFare added. 1.95 g (78%) of the expected derivative are obtained in theform of a brown oil.

[0243]¹H NMR (CDCl₃): 1.28 to 1.30(m,12H); 1.40(t,3H); 1.69(s,4H);4.41(q,2H); 7.12 to 7.59(m,4H); 8.24(dd,1H); 9.16(d,1H).

[0244] (d)6-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid

[0245] In a manner similar to that of Example 7, by reaction of 600 mg(1.36 mmol) of ethyl6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinatein 30 ml of THF and 1 g of sodium hydroxide, and after trituration fromheptane, 200 mg (36%) of the expected compound are obtained in the formof a yellow solid. m.p.=128° C.

[0246]¹H NMR (CDCl₃): 1.27 to 1.30(m,12H); 1.68(s,4H); 7.26 to7.52(m,5H); 8.32(d,1H); 9.26(s,1H)

[0247]¹³C NMR (CDCl₃): 31.8; 4CH3/34.2; Cq/34.6; Cq/34.8; CH2/34.9;CH2/78.6; Cq/101.4; Cq/123.6; Cq/123.8; Cq/125.8; CH/127.8; CH/128.4;CH/128.5; 137.9; CH/145.1; Cq/146.8; Cq/147.0; Cq/151.5; CH/169.0; Cq.

Example 10N-(4-hydroxyphenyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide

[0248] A solution of 250 mg (0.63 mmol) of4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid obtained in Example 5, 169 mg (1.25 mmol) of1-hydroxybenzoctriazole, 240 mg (1.25 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperaturefor 15 h. Water and ethyl acetate are then added. After stirring andseparation of the phases by settling, the aqueous phase is extractedwith ethyl acetate. The organic phases are then combined and washed withwater, dried over magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. The product is purified on a column ofsilica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid areobtained. m.p.=202° C.

[0249]¹H NMR (DMSO): 1.23 (s, 6H); 1.25 (s, 6H); 1.64 (s, 4H); 6.72 to6.76 (d, 2H); 7.39 (c, 1H); 7.51 to 7.55 (d, 2H); 7.59 to 7.61 (d, 2H);7.64 to 7.67 (d, 2H); 7.95 to 7.98 (d, 2H); 9.28 (s, 1H); 10.10 (s, 1H).

Example 11 Methyl5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate

[0250] (a) Methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate

[0251] In a manner similar to that of Example 1(a) starting with 7 g(26.6 mmol) of methyl 5-iodo-2-pyridinecarboxylate, 4.25 g (63%) of theexpected compound are obtained in the form of an orange-coloured powder.m.p.=45° C.

[0252]¹H NMR (CDCl₃) δ0.28 (s, 9H), 4.01 (s, 3H), 7.87 (dd, 1H,J=8.1/2.0 Hz), 8.08 (d, 1H, J=8.1 Hz), 8.77 (d, 1H, J=1.3 Hz).

[0253] (b) Methyl 5-ethynyl-2-pyridinecarboxylate

[0254] In a manner similar to that of Example 6(b), starting with 2.25 g(9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380mg (24%) of the expected compound are obtained in the form of a yellowpowder. m.p.=40-5° C.

[0255]¹H NMR (CDCl₃) δ3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H,J=8.1/2.0 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).

[0256] (c) Methyl5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate

[0257] In a manner similar to that of Example 4(b), after reaction of918 mg (1.73 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-diselenide in 2 mlof THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.62 g; 8.5mmol) and methyl 5-ethynyl-2-pyridinecarboxylate (500 mg; 3.1 mmol) in10 ml of DMF are added. After trituration from heptane, 420 mg (32%) ofthe expected derivative are obtained in the form of a yellow solid.m.p.=75° C.

[0258]¹H NMR (CDCl₃): 1.28 to 1.29(d,12H); 1.69(s,4H); 4.02(s,3H); 7.27to 7.37(m,2H); 7.54(d,1H); 7.84(dd,1H); 8.11(d,1H); 8.77(s,1H).

[0259]¹³C NMR (CDCl₃): 31.7; 4CH3/34.2; Cq/34.6; Cq/34.8; 2CH/53.0;CH3/79.2; Cq/98.3; Cq/123.9; 2Cq/124.5; CH/127.4; CH/128.2; CH/128.3;CH/138.7; CH/145.1; CH/145.8; Cq/146.9; Cq/151.6; CH/165.2; Cq.

Example 122-(4-Chlorophenylselanylethynyl)-5,5,8,8,tetramethyl-5,6,7,8-tetrahydronaphthalene

[0260] In a manner similar to that of Example 4(b), after reaction of 2g (5.25 mmol) of bis(4-chlorophenyl) diselenide in 5 ml of THF withbromine (0.266 ml, 5.15 mmol), copper iodide (4.11 g: 21.6 mmol) and6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (2.18 g; 10mmol) (described in patent application EP 0,661,258 A1) in 20 ml of DMFare added, and after purification on a column of silica (heptane), 1.85g (45%) of the expected derivative are obtained in the form of acolourless oil.

[0261]¹H NMR (CDCl₃): 1.28(s,12H); 1.68(s,4H); 7.26 to 7.30(m,4H); 7.46to 7.52(m,3H).

Example 13 Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0262] (a) 5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide

[0263] In a manner similar to that of Example 4(a), by reaction of 4.4 g(15.8 mmol) of2-bromo-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene) with 22 mlof tert-butyllithium and selenium (1.33 g, 16.8 mmol) in 100 ml of THF,3.26 g (74%) of the expected selenated derivative are obtained in theform of a yellow solid. (m.p.=126° C.).

[0264]¹H NMR (CDCl₃): 1.14(6H, s), 1.23 (6H, s), 1.61 (4H, s), 2.35 (3H,s), 7.05 (1H Ar, s), 7.55 (1H Ar, s).

[0265] (b) Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro2-naphthylselanylethynyl)benzoate

[0266] In a manner similar to that of Example 4(b), after reaction of1.5 g (2.75 mmol) of5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide in 5ml of THF, with bromine (0.15 ml, 2.9 mmol), copper iodide (2.1 g; 11.05mmol), and methyl 4-ethynylbenzoate (790 mg; 4.94 mmol) in 20 ml of DMFare added, and after trituration from heptane, 1.57 g (70%) of theexpected derivative are obtained in the form or a white solid. m.p.=104°C.

[0267]¹H NMR (CDCl₃): 1.27 to 1.29(m,12H); 1.68(s,4H); 2.36(s,3H);3.91(s,3H); 7.12(s,1H); 7.50(d,2H); 7.73(s,1H); 8.00(d,2H).

[0268]¹³C NMR (CDCl₃): 21.4; CH3/32.3; 2CH3/32.4; 2CH3/34.5; Cq/34.8;Cq/35.5; 2CH2/52.7; CH3/75.0; Cq/102.2; Cq/125:9; Cq/128.5; Cq/129.1;2CH/129.8; Cq/130.1; 2CH/131.5; 2CH/134.9; Cq/144.7; Cq/145.3; Cq/167.0;Cq.

Example 144-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoicacid

[0269] In a manner similar to that of Example 7, by reaction of 1.35 g(3.07 mmol) of methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoatein 20 ml of THF and 3 g of sodium hydroxide, and after trituration fromheptane, 1.05 g (80%) of the expected compound are obtained in the formof a white solid. m.p.=240° C.

[0270]¹H NMR (CDCl₃): 1.27 to 1.30(m,12H); 1.68(s,4H); 2.35(s,3H);7.13(s,1H); 7.50(d,2H); 7.71(s,1H); 8.00(d,2H).

[0271]¹³C NMR (CDCl₃): 20.5; CH3/31.5; 4CH3/33.6; Cq/33.9; Cq/34.6;2CH2/73.6; Cq/101.6; Cq/125.0; Cq/127.1; Cq/127.9; CH/128.3; CH/129.4;2CH/130.5; 2CH/133.8; Cq/143.9; 2Cq/144.5; Cq/167.5; Cq.

Example 15Methyl-2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoate

[0272] In a manner similar to that of Example 4(b), after reaction of 1g (1.78 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), copperiodide (1.36 g; 7.15 mmol) and methyl 4-ethynyl-2-hydroxybenzoate (566mg; 3.2 mmol) obtained according to Example 6(b) in 10 ml of DMF areadded, and after trituration from heptane, 715 mg (49%) of the expectedderivative are obtained in the form of a brown solid. m.p.=102° C.

[0273]¹H NMR (CDCl₃): 1.20(s,6H); 1.23(s,6H); 1.60(s,4H); 2.28(s,3H);3.87(s,3H); 6.87(dd,1H); 6.97(d,1H); 7.04(s,1H); 7.64(s,1H); 7.71(d,1H);10.70(s,1H).

[0274]¹³C NMR (CDCl₃): 20.7; CH3/31.7; 4CH3/33.8; Cq/34.1; Cq/34.8;2CH2/74.9; Cq/101.4; Cq/111.7; Cq/119.4; Cq/121.6; CH/125.1; Cq/128.4;2CH/129.7; CH/130.3; Cq/134.2; Cq/144.1; Cq/144.7; Cq/161.1; Cq/169.9;Cq.

Example 162-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

[0275] In a manner similar to that of Example 7, by reaction of 500 mg(1.1 mmol) of methyl2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,in 20 ml of THF, with 500 mg of sodium hydroxide, 464 mg (99%) of theexpected compound are obtained in the form of a brown solid. m.p.=248°C.

[0276]¹H NMR (CDCl₃+DMSO): 0.89(s,6H); 0.92(s,6H); 1.30(s,4H);1.96(s,3H); 6.55(dd,1H); 6.60(s,1H); 7.31(s,1H) 7.43(d,1H);10.96(sb,1H).

[0277]¹³C NMR (CDCl₃+DMSO): 20.6; CH3/31.6; 4CH3/34.0; Cq/34.6; Cq/34.7;2CH2/74.1; Cq/101.6; Cq/112.5; Cq/118.9; CH/121.3; CH/125.0; Cq/128.0;CH/128.3; CH/129.6; Cq/130.4; CH/133.9; Cq/144.0; Cq/144.0; Cq/144.5;Cq/161.4; Cq/171.9; Cq.

Example 17 Ethyl6-(3,5,5,9,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate

[0278] In a manner similar to that of Example 4(b), after reaction of 1g (1.78 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide, in 5 ml of THF, with bromine (0.092 ml, 1.78 mmol), copperiodide (1.36 g; 7.15 mmol) and ethyl 6-ethynylnicotinate (463 mg; 2.64mmol) in 10 ml of DMF are added, and 1.06 g (88%) of the expectedderivative are obtained in the form of a brown solid. m.p.=95° C.

[0279]¹H NMR (CDCl₃): 1.20(s,6H); 1.24(s,6H); 1.34(t,3H); 1.61(s,3H);4.33(q,2H); 7.07(s,1H); 7.38(d,1H); 7.67(s,1H); 8.17(dd,1H); 9.08(d,1H).

[0280]¹³C NMR (CDCl₃): 13.9; CH3/20.9; CH3/31.5; 4CH3/33.7; Cq/34.0;Cq/34.6; 2CH2/61.2; CH2/77.2; Cq/101.2; Cq/124.2; Cq/124.3; Cq/125.2;Cq/128.4; Cq/129.4; Cq/134.8; Cq/136.8; Cq/144.0; Cq/145.1; Cq/146.3;Cq/150.8; Cq/164.5; Cq.

Example 186-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid

[0281] In a manner similar to that of Example 7, by reaction of 800 mg(1.73 mmol) of ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,in 20 ml of THF, with 800 mg of sodium hydroxide, and after purificationor a column of silica (ethyl acetate), 135 mg (19%) of the expectedcompound are obtained in the form of a yellow solid. m.p.=185° C.

[0282]¹H NMR (CDCl₃): 1.27(s,6H); 1.31(s,6H); 1.68(s,4H); 2.40(s,3H);7.15(s,1H); 7.26(s,1H); 7.49(d,1H); 7.74(s,1H); 8.32(d,1H); 9.25(s,1H).

[0283]¹³C NMR (CDCl₃): 21.7; CH3/32.2; 4CH3/34.5, Cq/34.7; Cq/35.3;2CH2/78.9; Cq/101.7; Cq/124.0; Cq/124.9; Cq/126.1; CH/129.1; CH/130.2;CH/135.6; Cq/1382; CH/144.8; Cq/145.9; Cq/147.6; Cq/152.0; CH/169.5; Cq.

Example 19N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinamide

[0284] In a manner similar to that of Example 10, by reaction of 300 mg(0.72 mmol) of the6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinicacid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45mmol) of 1,3-dicyclohexylcarbodiimide and 95 mg (0.87 mmol) of4-aminophenol in 20 ml of THF, and after purification on a column ofsilica (ethyl acetate 20/heptane 80), 20 mg (6%) of a yellow solid areobtained. m.p.=172° C.

[0285]¹H NMR (DMSO): 1.17 to 1.19(m,12H); 1.56(s,4H); 2.27(s,3H);6.68(d,2H); 7.21(s,1H); 7.46(d,2H); 7.58(d,1H); 7.64(s,1H); 8.22(dd,1H);8.99(s,1H)9.30(s, 1H); 10.2(s, 1H).

[0286]¹³C NMR (DMSO): 31.6; 4CH3/33.5; CH2/33.8; CH2/34.0;Cq/34.5,Cq/47.6; CH3/74.9; Cq/102.0; Cq/115.2; 2CH/122.3; 2CH/124.4;Cq/125.9; CH/128.7; CH/128.9; CH/130.4; Cq/134.8; Cq/136.1; CH/144.0;Cq/144.1; Cq/145.1; Cq/149.3; Cq/154.1; Cq/156.8; Cq.

Example 20N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide

[0287] In a manner similar to that of Example 10, 300 mg (0.72 mmol) of6-(3,5,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol)of butylamine in 20 ml of THF. After purification on a column of silica(ethyl acetate 20/heptane 80), 60 mg (17%) of a yellow solid areobtained. m.p.=172° C.

[0288]¹H NMR (CDCl₃): 0.97(t,3H); 1.27 to 1.37(m,12H); 1.37 to1.46(m,4H); 1.68(s,4H); 2.39(s,3H); 3.47(q,2H) 6.13(m,1H) 7.14(s,1H);7.46(d,1H); 7.74(s,1H); 8.07(dd,1H); 8.87(s, 1H).

[0289]¹³C NMR (CDCl₃) 31.8; CH3/20.2; CH2/21.2; CH3/31.7; 4CH3/34.0;Cq/34.3; Cq/35.0; 2CH2/40.0; CH2/76.2; Cq/101.2; Cq/124.7 Cq/126.0;CH/128.7; CH/129.7; CH/; CH/35.1; Cq/135.3; CH;/144.3; Cq/145.4;Cq/145.5; Cq/; Cq.

Example 21Morpholin-4-yl-[6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone

[0290] In a manner similar to that of Example 10, 300 mg (0.72 mmol) of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 75.7 mg (0.87 mmol)of morpholine in 20 ml of THF. After purification on a column of silica(ethyl acetate 20/heptane 80), 60 mg (17%) of a colourless oil areobtained.

[0291]¹H NMR (CDCl₃): 1.27 to 1.32(m,12H); 1.68(s,4H); 2.39(s,3H);3.81(sbr,8H); 7.13(s,1H); 7.45(d,1H); 7.71 to 7.75(m,2H); 8.61(d,1H).

[0292]¹³C NMR (CDCl₃): 21.2; CH3/31.8; 4CH3/34 1; Cq/34.3; Cq/35.0;2CH2/66.8; 4CH2/75.5; Cq/101.1; Cq/124.7; Cq/126.0; CH/128.7; CH/129.4;Cq/129.7; CH/135.1; Cq/135.5; CH/144.3; Cq/144 5; Cq/145.4; Cq/148.3;CH/167.4; Cq.

Example 22 Methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate

[0293] In a manner similar to that of Example 4(b), after reaction of945 mg (1.68 mmol) of5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide, in 5ml THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.32 g; 6.95mmol) and methyl 5-ethynyl-2-pyridinecarboxylate (500 mg; 3.1 mmol) in10 ml of DMF are added, and after trituration from heptane, 1 g (73%) ofthe expected derivative is obtained in the form of a yellow solid.m.p.=52° C.

[0294]¹H NMR (CDCl₃) 1.27 to 1.29(m,12H); 1.68(s,4H); 2.37(s,3H);4.02(s,3H) 7.14(s,1H); 7.71(s,1H); 7.85(dd,1H) 8.02(s,1H) 8.11(d,1H).

[0295]¹³C NMR (CDCl₃): 20.7; CH3/31.5; 2CH3/31.6; 2CH3/33.7; Cq/34.0;Cq/34.6; 2CH2/52.7; CH3/78; Cq/98.1; Cq/123.7; Cq/124.2;CH/124.5;Cq/128.4; CH/128.5; CH/134.3;Cq/138.3; CH/144.0; Cq/144.9;Cq/145.5;Cq/151.2; CH/162.2; Cq.

Example 235-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecazboxylicacid

[0296] In a manner similar to that of Example 7, by reaction of 800 mg(1.73 mmol) of methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate,in 20 ml of THF, with 2 g of sodium hydroxide, and after triturationfrom heptane, 580 mg (65%) of the expected compound are obtained in theform of a white solid. m.p.=164° C.

[0297]¹H NMR (CDCl₃): 1.28(s,6H); 1.30(s,6H); 1.69(s,4H); 2.39(s,3H);7.16(s,1H); 7.69(s,1H); 7.93(d,1H); 8.17(dbr,1H); 8.66(sbr,1H).

[0298]¹³C NMR (CDCl₃): 21.2; CH3/31.8; 2CH3/3.9; 2CH3/34.1; Cq/34.3;Cq/34.9; 2CH2/124.6; Cq/128.8; CH/129.3; CH/134.9; Cq/139.8; CH/144.4;2Cq/145.5; 2Cq.

Example 24[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethyl)-phenyl]methanol

[0299] A 1M solution of diisobutylaluminium hydride in toluene (4 ml, 4mmol) is added dropwise, at 0° C., to a solution of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-benzoateobtained according to Example 4 (750 mg, 1.8 mmol), in toluene (20 ml)The solution is stirred for 4 h at 0° C. and is then treated with adouble potassium sodium tartrate solution, filtered and taken up in amixture of ethyl ether and water. The organic phase is washed withwater, dried over magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. 418 mg (60%) of a colourless oil areobtained.

[0300]¹H NMR (CDCl₃): 1.26(s, 6H), 1.28(s, 6H), 1.76(s, 4H), 4.67(s,2H), 7.24 to 7.37(m, 4H), 7.46(d, 2H, J=8.2 Hz), 7.52(d, 1H, J=1.9 Hz).

Example 25 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)-benzoate

[0301] In a manner similar to that of Example 1(c), by reaction of 234mg (1.1 mmol) of6-ethynyl-1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronaphthalene, in 5 ml ofTHF, with 2.5 M butyllithium (0.4 ml, 1 mmol) and 2,2′-dithiobis(methylbenzoate) (267 mg; 0.8 mmol), and after purification on a column ofsilica (dichloromethane 30/heptane 70), the expected derivative isobtained in the form of a white solid.

[0302]¹H NMR (CDCl₃): 1.28(6H, s), 1.29(6H, s), 1.69(4H, s), 3.91(3H,s), 7.30(2H Ar, s), 7.49 to 7.54(3H Ar, m), 8.0(2H Ar, d, J=6.9 Hz).

Example 264-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol

[0303] (a) 4-Trimethylsilylethynylphenyl acetate

[0304] In a manner similar to that of Example 1(a), starting with 4.63 g(17.7 mmol) of 4-iodophenyl acetate, 3.72 g (90%) of the expectedcompound are obtained in the form of a yellow powder. m.p.=45° C.

[0305]¹H NMR/CDCl₃: 0.05(s; 9H); 2.10(s,3H); 6.84(dt,2H); 7.28(dt,2H).

[0306]¹³C NMR/CDCl₃: 0.00; 2CH3/21.2; CH3/94.4; Cq/104.3; Cq/120.9;Cq/121.2; 2CH/133.2; 2CH/150.7; Cq/169.1; Cq.

[0307] (b)4-5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenylacetate

[0308] In a manner similar to that of Example 4(b), after reaction of1.39 g (2.4 mmol) of5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene diselenide, in THF,with bromine (0.22 ml, 4.3 mmol), copper iodide (1.82 g, 9.6 mmol) and4-trimethylsilylethynylphenyl acetate ester (1 g; 4.3 mmol) in DMF areadded at 80° C. for 15 h, and after purification on a column of silica(dichloromethane 20/heptane 80), 220 mg (16%) of the expected derivativeare obtained in the form of a yellow oil.

[0309]¹H NMR/CDCl₃: 1.19(d,12H); 1.59(s,4H); 2.22(s,3H); 2.26(s,3H);6.97 to 7.02(m,3H); 7.39 to 7.42(dd,2H); 7.65(s,1H).

[0310]¹³C NMR/CDCl₃ 19.2; CH3/19.5; CH3/30.3; 4CH3/32.4; Cq/32.7;Cq/33.4; CH2/33.5; CH2/68.7; Cq/99.9; Cq 119.5; Cq/120.1; 2CH/124.2;Cq/126.7; CH/126.9; C/131.0; 2CH/133.0; Cq/142.5; Cq/143.5; Cq/138.0;Cq/167.5; Cq.

[0311] (c)4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol

[0312] A mixture of4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)phenylacetate (500 mg, 1.1 mmol) and potassium carbonate (160 mg, 1.1 mmol) inmethanol (20 ml) is stirred for 24 h at room temperature and is thentreated with ethyl ether and water. The organic phase is washed twicewith water, dried over anhydrous magnesium sulphate and concentrated ona rotary evaporator under vacuum at 40° C. The product is purified on acolumn of silica (ethyl acetate 20/heptane 80). 300 mg (66%) of a clearoil are obtained.

[0313]¹H NMR/CDCl₃: 1.25 to 11.27(m,12H); 1.66(s,4H); 2.35(s,3H);6.77(d,2H); 7.09(s,1H); 7.38(dd,2H); 7.73(s,1H).

[0314]¹³C NMR/CDCl₃: 20.3; CH3/31.4; 4CH3/33.6; 2Cq/34.6; 2CH2/67.2;Cq/103.7; Cq/115.3; Cq/115.6; 2CH/127.7; Cq/128.5; 2CH/133.0; 2CH/133.6;Cq/143.6; Cq/143.9; Cq/156.0; Cq.

Example 27 Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0315] In a manner similar to that of Example 4(b), after reaction of 1g (1.5 mmol) of4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenediselenide, in THF, with bromine (0.092 ml, 1.78 mmol), copper iodideand ethyl 4-trimethylsilylethynylbenzoate (644 mg; 2.8 mmol) in DMF areadded at 80° C. for 15 h. After purification on a column of silica(dichloromethane 20/heptane 80), 220 mg (16%) of the expected derivativeare obtained in the form of a yellow oil.

[0316]¹H NMR/CDCl₃: 1.29(s,6H); 1.37 to 1.43(m,9H); 1.65(q,4H);4.39(q,2H); 5.72(s,1H); 7.26(s,1H); 7.43(s,1H); 7.55(d,2H); 8.03(d,2H)

Example 28 Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

[0317] In a manner similar to that of Example 4(b), after reaction of 1g (1.5 mmol) of4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenediselenide, in THF, with bromine (0.092 ml, 1.78 mmol), copper iodideand ethyl 4-trimethylsilylethynylbenzoate (644 mg 2.8 mmol) in DMF areadded at 80° C. for 15 h. After purification on a column of silica(dichloromethane 20/heptane 80), 420 mg (31%) of the expected derivativeare obtained in the form of a yellow oil.

[0318]¹H NMR/CDCl₃: 1.17(q,6H); 1.31(m,9H); 1.49 to 1.57(m,4H);3.38(s,3H); 4.25(q,2H); 5.10(s,2H); 7.08(d,1H); 7.14(d,1H); 7.41(d,2H);7.88(d,2H).

Example 294-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

[0319] In a manner similar to that of Example 7, by reaction of 300 mgof ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoateester in 30 ml of THF with 500 mg of sodium hydroxide, and aftertrituration from heptane, the expected compound is obtained in the formof a white solid.

[0320]¹H NMR/CDCl₃: 1.28 (s, 6H); 1.39 (s, 6H); 1.66 (m, 2H); 3.51 (s,3H); 5.23 (s, 2H); 7.19 (d, 1H, J=1.8 Hz); 7.25 (d, 1H, J=1.8 Hz); 7.56(d,2H, J=8.5 Hz); 8.06 (d,2H, J=8.5 Hz).

Example 30[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-phenyl]carbaldehyde

[0321] A mixture of[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-phenyl]methanolobtained in Example 24 (280 mg, 0.7 mmol) and pyridinium dichromate (526mg, 1.4 mmol) in dichloromethane (10 ml) is stirred at room temperaturefor 4 h. After filtration through silica and concentration on a rotaryevaporator under vacuum at 40° C., 173 mg (63%) of the expected productare obtained in the form of a yellow oil.

[0322]¹H NMR/CDCl₃: 1.28 (s, 6H), 1.30 (s, 6H), 1.70 (s, 4H), 4.67 (s,2H), 7.23 (1H Ar, d, J=8.3 Hz), 7.29 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz),7.52 to 7.59 (3H Ar, m), 7.84 (1H Ar, d, J=6.7 Hz); 9.99 (.H, s).

Example 31 Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynylbenzoate

[0323] (a) 2-Bromo-1-(3-methylbut-2-enylthio)benzene

[0324] 19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and15.50 g (112.0 mmol) of potassium carbonate are introduced into athree-necked flask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene areadded dropwise and the mixture is stirred at room temperature for twohours. The reaction medium is poured into water and extracted with ethylacetate, and the organic phase is separated out after settling has takenplace, washed with water, dried over magnesium sulphate and evaporated.26.00 g (99%) of the expected compound are collected in the form of anorange-coloured oil.

[0325]¹H NMR/CDCl₃ d 1.65 (s, 3H), 1.73 (s, 3H), 3.56 (d, 2H, J=7.7 Hz),5.32 (td, 1H, J=7.7/1.4 Hz), 6.96 to 7.06 (m, 1H), 7.22 to 7.26 (m, 2H),7.52 (d, 1H, J=7.7 Hz).

[0326] (b) 4,4-Dimethyl-8-bromothiochroman

[0327] 26.00 g (102.0 mmol) of2-bromo-1-(3-methylbut-2-enylthio)benzene, 180 ml of toluene and 23.20 g(122.0 mmol) of para-toluenesulfonic acid are introduced into athree-necked flask. The reaction medium is refluxed for four hours andevaporated to dryness. The residue is taken up in aqueous sodiumhydrogen carbonate solution and extracted with ethyl acetate, and theorganic chase is separated out after settling has taken place, driedover magnesium sulphate and evaporated. The residue obtained is purifiedby chromatography on a column of silica eluted with heptane. 20.00 g(76%) of the expected compound are collected in the form of anorange-coloured oil.

[0328]¹H NMR (CDCl₃) d 1.33 (s, 6H), 1.94 (t, 2H, J=6.0 Hz), 3.04 (t,2H, J=6.1 Hz), 6.89 (t, 1H, J=7.9 Hz), 7.34 (d, 2H, J=7.9 Hz).

[0329] (c) 4,4-Dimethyl-8-thiochromain diselenide

[0330] One crystal of iodine, magnesium (208 mg, 8.56 mmol) and a fewdross of a solution of 4,4-dimethyl-8-bromothiochroman (2 g, 7.78 mmol)in ethyl ether (15 ml) are heated until the organomagnesium reagent hasbeen initiated. The rest of the solution is then added dropwise. Thereaction medium is heated for 2 h and selenium (615 mg, 7.78 mmol) isthen added at room temperature. The stirring is continued for 30 min and1N HCl solution is then added. The reaction mixture is treated withethyl ether. The organic phase is washed twice with water, dried overanhydrous magnesium sulphate and concentrated on a rotary evaporatorunder vacuum at 40° C. Ethanol and sodium hydroxide are added to the oilobtained. The mixture is stirred vigorously for a few minutes and isthen concentrated on a rotary evaporator under vacuum at 40° C. Theproduct is purified on a column of silica (dichloromethane 20/heptane80). 300 mg (15%) of a white solid are obtained.

[0331]¹H NMR (CDCl₃): 1.33 (6H, s), 1.96 (2H, m), 3.09 (2H, m), 6.93 (1HAr, t, J=7.8 Hz), 7.26 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 7.47 (1H Ar, dd,J=7.8 Hz, J=1.3 Hz).

[0332] (c) Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynyl)benzoate

[0333] In a manner similar to that of Example 4(b), after reaction of300 mg (1.9 mmol) of 4,4-dimethyl-8-thiochroman diselenide, in 2 ml ofTHF, with bromine (0.117 ml, 2.2 mmol), cooper iodide (780 mg) andmethyl 4-ethynylbenzoate (562 mg; 3.5 mmol) in 20 ml of DMF are added,and after purification on a column of silica (dichloromethane 20/heptane80), the expected derivative is obtained in the form of a yellow solid.

[0334]¹H NMR (CDCl₃): 1.35 (6H, s), 1.97 (2H, m), 3.10 (2H, m), 3.93(3H, s), 7.07 (1H Ar, t, J=7.8 Hz), 7.31 (1H Ar, dd, J=7.8 Hz, J=1.3Hz), 7.55 (2H Ar, d, J=8.5 Hz) 7.59 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz),8.00 (2H Ar, d, J=8.5 Hz).

Example 324-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoicacid

[0335] In a manner similar to that of Example 2, by reaction of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoatein THF, and after crystallization from heptane, the expected derivativeis obtained in the form of white solid.

[0336]¹NMR (CDCl₃): 1.28 (6H, s), 1.29 (6H, s), 1.70 (4H, s), 7.30 (2HAr, s), 7.43 to 7.50 (3H Ar, t), 7.99 (2H Ar, d, J=7.5 Hz).

Example 334-(6-bromo-4,4-dimethyl-thiochroman-8-ylselanylethynyl)-benzoic acid

[0337] a) 4,4,Dimethyl-thiochroman-8-diselenide.

[0338] One crystal of iodine, magnesium (1.46 g, 60 mmol) and few dropsof a solution of 4,4-dimethyl-8-bromothiochroman (10.3 g, 40 mmol) inTHF (100 ml) are heated until the organomagnesium reagent has beeninitiated. The rest of the solution is then added dropwise. The reactionmixture is heated for 2 h and selenium (3.48 g, 44 mmol) is then addedat room temperature. The stirring is continued for 2 h and 1N HClsolution is then added. The reaction mixture is treated with ethylether. The organic phase is washed twice with water, dried overanhydrous magnesium sulphate and concentrated on a rotary evaporatorunder vacuum at 40° C. Ethanol (25 ml) and sodium hydroxide (126 mg) areadded to the oil obtained. The mixture is stirred vigorously for a nightand is then filtered. The solid obtained is dissolved in a minimalamount of dichloromethane and then purified on silica cake.

[0339] A yellow solid is obtained. Weight 8.66 g, yield 84%.

[0340]¹H (CDCl₃): 1.33 (6H, s), 1.96 (2H, m), 3.09 (2H, m), 6.93 (1H Ar,t, J=7.8 Hz), 7.26 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 7.47 (1H Ar, dd,J=7.8 Hz, J=1.3 Hz).

[0341] b) 6-Bromo-4,4-dimethyl-8-bromoselenythiochromane.

[0342] A bromide solution (3 ml, 58.5 mol) in CCl₄ (50 ml) is addeddropwise to a solution of 4,4-Dimethyl-thiochromane-8-diselenide (6 g,11.7 mmol) in CCl₄ (200 ml). The reaction mixture is stirred 40 h atroom temperature, concentrated at a dried state on a rotary evaporatorunder vacuum at 40° C., then recovered in a mixturedichloromethane/heptane and concentrated again.

[0343] A clear brown powder is obtained. Weight 9.48 g. Yield 98%.

[0344]¹H (CDCl₃): 1.34 (6H, s), 1.95 (2H, m), 3.09 (2H, m), 7.43 (1H Ar,d, J=1.9 Hz), 7.66 (1H Ar, d, J=1.9 Hz).

[0345] c)Methyl-4-(6-bromo-4,4-dimethyl-thiochroman-8-ylselanylethynyl)-benzoate

[0346] Copper iodide (8.26 g, 10.8 mmol),methyl-4-ethynyl-2-hydroxybenzoate (1.73 g, 10.8 mmol) obtainedaccording to the example 1(b) are added to a solution of6-Bromo-4,4-dimethyl-8-bromoselenythiochromane (4.95 g, 11.9 mmol) inDMF (60 ml). the reaction mixture is stirred at room temperature for 20h, then treated with ethyl ether and ammoniac solution. The organicphase is washed twice with water, dried over anhydrous magnesiumsulphate and concentrated on a rotary evaporator under vacuum at 40° C.The product is purified on fast plug with a solvent gradient based onheptane-ethylacetate.

[0347] Clear brown powder. Weight 3.38 g. Yield 63%.

[0348]¹H (CDCl₃): 1.34 (6H, s), 1.95 (2H, m), 3.10 (2H, m), 3.93 (3H,s), 7.40 (1H Ar, d, J=2.0 Hz), 7.54 (2H Ar, dd, J=1.7 Hz, J=6.7 Hz),7.74 (1H Ar, d, J=2.0 Hz), 8.02 (2H Ar, dd, J=1.7 Hz, J=6.7 Hz).

[0349] d)4-(6-bromo-4,4-dimethyl-thiochroman-8-ylselanylethynyl)-benzoic Acid.

[0350] In a manner similar to that of Example 5, with 395 mg (0.8 mmol.)of methyl4-(6-bromo-4,4-dimethyl-thiochroman-8-ylselanycethynyl)-benzoate, theexpected acid is obtained in the form of a white powder. Weight 192 mg.Yield 50%.

[0351]¹H (CDCl₃): 1.29 (6H, s), 1.96 (2H, m), 3.11 (2H, m), 3.93 (3H,s), 7.40 (1H Ar, d, J=1.9 Hz), 7.55 (2H Ar, d, J=8.3 Hz), 7.73 (1H Ar,d, J=1.9 Hz), 8.04 (2H Ar, d, J=8.3 Hz).

[0352]¹³C (CDCl₃): 24.11 (CH2), 29.84 (2 CH3), 33.83 (C), 33.80 (CH2),72.75 (C), 104.27 (C), 118.46 (C), 128.01 (C), 127.97 (CH), 128.98 (C),129.21 (CH), 129.79 (2CH), 131.20 (2CH), 145.26 (C), 167.83 (C).

FORMULATION EXAMPLES Example 1

[0353] Various pharmaceutical and cosmetic formulations based on thecompounds according to the invention are described below.

[0354] A—Oral Route (a) 0.2 g tablet Compound of Example 1 10.001 gStarch 0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030g Talc 0.010 g Magnesium stearate 0.005 g

[0355] In this example, the compound of Example 1 can be replaced withthe same amount of one of the compounds of Examples 4, 6, 11, 13 or 15.(b) Drinkable suspension in 5 ml vials Compound of Example 3 20.001 gGlycerol 0.500 g 70% sorbitol 0.500 g Sodium saccharinate 0.010 g Methylp-hydroxybenzoate 0.040 g Flavouring, qs Purified water qs 5 ml (c) 0.8g tablet Compound of Example 2 0.500 g Pregelatinized starch 0.100 gMicrocrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate0.010 g

[0356] In this example, the compound according to Example 2 can bereplaced with the same amount of one of the compounds of Examples 6, 11,14 or 28. (d) Drinkable suspension in 10 ml vials Compound of Example 30.200 g Glycerol 1.000 g 70% sorbitol 1.000 g Sodium saccharinate 0.010g Methyl p-hydroxybenzoate 0.080 g Flavouring, qs Purified water qs 10ml

[0357] B—Topical Route (a) Ointment Compound of Example 2 20.020 gIsopropyl myristate 81.700 g Fluid liquid petroleum jelly 9.100 g Silica(“Aerosil 200” sold by 9.180 g Degussa) (b) Ointment Compound of Example1 0.300 g White petroleum jelly codex 100 g (c) Nonionic water-in-oilcream Compound of Example 1 0.100 g Mixture of emulsifying lanolin39.900 g alcohols, waxes and oils (“anhydrous eucerin” sold by BDF)Methyl p-hydroxybenzoate 0.075 g Propyl p-hydroxybenzoate 0.075 gSterile demineralized water qs 100 g

[0358] In this example, the compound according to Example 1 can bereplaced with the same amount of one or the compounds of Examples 4, 16,22, 27 or 32. (d) Lotion Compound of Example 3 0.100 g Polyethyleneglycol (PEG-400) 69.900 g 95% ethanol 30.000 g (e) Hydrophobic ointmentCompound of Example 1 0.300 g Isopropyl myristate 36.400 g Silicone oil(“Rhodorsil 47V300” sold by Rhône-Poulenc) 36.400 g Beeswax 13.600 gSilicone oil (“Abil 300.000 cst” sold by Goldschmidt) 100 g (f) Nonionicoil-in-water cream Compound of Example 2 1.000 g Cetyl alcohol 4.000 gGlyceryl monostearate 2.500 g PEG stearate 502.500 g Karite butter 9.200g Propylene glycol 12.000 g Methyl p-hydroxybenzoate 0.075 g Propylp-hydroxybenzoate 0.075 g Sterile demineralized water 100 g

[0359] In this example, the compound according to Example 2 can bereplaced with the same amount of one of the compounds of Examples 5, 9,12, 19 and 32.

Test of Activity

[0360] Results of differentiation tests on mouse embryonicteratocarcinoma cells (F9) to identify the RAR-agonist molecules asdescribed in Skin Pharmacol. 3, pp. 256-267, 1990.

[0361] After treatment with the compounds of the examples cited in thefollowing table, the mouse embryonic teratocarcinoma F9 cellsdifferentiate into endodermal cells. This differentiation ischaracterized by the secretion of the plasminogen activator into theculture medium.

[0362] The activity of the product is expressed by the AC₅₀ valuerepresenting the concentration of the test product which produces halfof the maximum amount of plasminogen activator secreted. Examples F9AC₅₀ (nM) Compound 1 20 Compound 2 1 Compound 4 4 Compound 5 21 Compound16 33 Compound 18 34

[0363] These results indicate that the compounds of Examples 1, 2, 4, 5,16 and 18 are RAR-agonist compounds. TABLE A

[0364] TABLE B

1. Bi-aromatic compounds linked via a heteroethynylene bond,characterized in that they correspond to the general formula (I) below:

in which: Ar represents a radical chosen from the formulae (a) to (c)below:

Z being O or S, or N—R₆, R₁ represents a halogen atom, —CH₃, —CH₂—OR₇,—OR₇, —COR₈ or a polyether radical, R₂ and R₃, which may he identical ordifferent, represent H, linear or branched C₁-C₂₀ alkyl, C₃-C₁₂cycloalkyl, —OR₇ or —SR7, at least one from among R₂ and R₃ being linearor branched C₁-C₂₀ alkyl or C₃-C₁₀ cycloalkyl, or R₂ and R₃, takentogether, form a 5- or 6-membered ring, optionally substituted with atleast one methyl and/or optionally interrupted by a hetero atom chosenfrom O and S, R₄ and R₅ represent H, a halogen atom, linear or branchedC₁-C₂₀ alkyl, —OR₇ or a polyether radical, R₆ represents H, linear orbranched C₁-C₁₀ alkyl or —OCOR₉, R₇ represents H, linear or branchedC₁-C₁₀ alkyl or —COR₉, R₈ represents H, linear or branched C₁-C₁₀,alkyl, —OR₁₀ or

R₉ represents linear or branched C₁-C₁₀ alkyl, R₁₀ represents H, linearor branched C₁-C₂₀ alkyl, mono- or polyhydroxyalkyl, allyl, optionallysubstituted aryl or aralkyl, or a sugar residue, r′ and r″, which may beidentical or different, represent H, C₁-C₁₀ alkyl, mono- orpolyhydroxyalkyl, optionally substituted aryl, an amino acid or peptideresidue, or, taken together with the nitrogen atom, form a heterocycle,X represents a divalent radical which, from right to left or vice-versa,has the formula:

in which: Y represents O, S(O)_(n) or Se(O)_(n′), n and n′ being 0, 1 or2, with the proviso that when n=2 and Ar is a radical of formula (a)above, in which R₁═—CH₃ and R₅═H, then at least one of the radicals R₂or R3 is other than —CH₃, and the salts of the compounds of formula (I)when R₁ represents a carboxylic acid function, as well as the opticalisomers of the said compounds of formula (I).
 2. Compounds according toclaim 1, characterized in that they are in the form of a salt of analkali metal or alkaline-earth metal, or alternatively of zinc or of anorganic amine.
 3. Compounds according to either of claims 1 and 2,characterized in that the C₁-C₁₀ alkyl radical is chosen from the groupconsisting of the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl,2-ethylhexyl and octyl radicals.
 4. Compounds according to any one ofthe preceding claims, characterized in that the linear or branchedC₁-C₂₀ alkyl radical is chosen from the group consisting of the methyl,ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecylradicals.
 5. Compounds according to any one of the preceding claims,characterized in that the C₃-C₁₂ cycloalkyl radical is chosen from thegroup consisting of the cyclopropyl, cyclopentyl, cyclohexyl,1-methylcyclohexyl and 1-adamantyl radicals.
 6. Compounds according toany one of the preceding claims, characterized in that the polyetherradical is chosen from the group consisting of the methoxymethoxy,methoxyethoxy and methoxyethoxymethoxy radicals.
 7. Compounds accordingto any one of the preceding claims, characterized in that themonohydroxyalkyl radical is chosen from the group consisting of the2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals. 8.Compounds according to any one of the preceding claims, characterized inthat the polyhydroxyalkyl radical is chosen from the group consisting ofthe 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl radicals and the pentaerythritol residue. 9.Compounds according to any one of the preceding claims, characterized inthat the aryl radical is a phenyl radical optionally substituted with atleast one halogen atom, a hydroxyl or a nitro function.
 10. Compoundsaccording to any one of the preceding claims, characterized in that thearalkyl radical is chosen from the group consisting of the benzyl andphenethyl radicals optionally substituted with at least one halogenatom, a hydroxyl or a nitro function.
 11. Compounds according to any oneof the preceding claims, characterized in that the sugar residue ischosen from the group consisting of the glucose, galactose, mannose andglucuronic acid residues.
 12. Compounds according to any one of thepreceding claims, cnaracterized in that the amino acid residue is chosenfrom the group consisting of the residues derived from lysine, fromglycine or from aspartic acid.
 13. Compounds according to any one of thepreceding claims, characterized in that the heterocyclic radical ischosen from the group consisting of the piperidino, morpholino,pyrrolidino and piperazino radicals, optionally substituted in position4 with a C₁-C₆ alkyl or a mono- or polyhydroxyalkyl.
 14. Compoundsaccording to any one of the preceding claims, characterized in that thehalogen atom is chosen from the group consisting of fluorine, chlorineand bromine.
 15. Compounds according to any one of the preceding claims,characterized in that they correspond to the following general formula:

in which: Ar′ represents a radical of formula:

R₁, R₄, R₅ and X being as defined in claim 1, R₁₁, R₁₂, R₁₃ and R₁₄,which may be identical or different, represent H or —CH₃, and n is 1 or2.
 16. Compounds according to any one of claims 1 to 14, characterizedin that they correspond to the following general formula

in which: W represents O or S, R₄, R₁₁, R₁₂, Ar′ and X being as definedin claim
 15. 17. Compounds according to any one of claims 1 to 14,characterized in that they correspond to the following general formula:

in which: R₄, Ar′ and X are as defined in claim 15, and at least one ofthe radicals R′₂ and/or R′₃ represents a mono- or polycyclic C₅-C₁₀cycloalkyl radical, the other representing one of the meanings given forR₂ and R₃ as defined in claim
 1. 18. Compounds according to any one ofthe preceding claims, characterized in that they are taken from thegroup consisting of: Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid, Methyl2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,2-Hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,6-(4-Methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,p0 Ethyl6-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,6-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,N-(4-Hydroxyphenyl)-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide,Methyl5-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate,2-(4-Chlorophenylselanylethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid, Methyl2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid, Ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,Morpholin-4-yl-[6-(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone,Methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)pyridine-2-carboxylate,5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)pyridine-2-carboxylicacid,[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol,Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate,Methyl4-(5,5,8,8tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoate,Methyl4-(5,5,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoicacid,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoicacid,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoicacid,4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol,Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,4-(4-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid, Ethyl4-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,Ethyl4-(3-methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3-Methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,4-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoicacid, Ethyl4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde,Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynyl)benzoate,4-(4,4-Dimethylthiochroman-8-ylselanylethynyl)benzoic acid, Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoate,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoicacid, Methyl4-[3-(1-adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoate,4-[3-(1-Adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoic acid,Methyl 4-[4-(1-adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoate,4-[4-(1-Adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoic acid, and4-(6-bromo-4,4-dimethyl-thiochroman-8-ylselanylethynyl)-benzoic acid.19. Compounds according to any one of the preceding claims, for use as amedicinal product.
 20. Compounds according to claim 19, for use as amedicinal product intended for the treatment of dermatologicalcomplaints, dermatological complaints with an inflammatory and/orimmunoallergic component of the rheumatic or respiratory type,cardiovascular complaints and opthalmological disorders.
 21. Use of atleast one of the compounds as defined according to any one of claims 1to 18, for the preparation of a medicinal product intended for thetreatment of dermatological complaints, dermatological complaints withan inflammatory and/or immunoallergic component of the rheumatic orrespiratory type, cardiovascular complaints and opthalmologicaldisorders.
 22. Pharmaceutical composition, characterized in that itcomprises, in a pharmaceutically acceptable support, at least onecompound as defined according to any one of claims 1 to
 18. 23.Composition according to claim 22, characterized in that theconcentration of at least one compound according to one of claims 1 to18 is between 0.001% and 5% by weight relative to the total weight ofthe composition.
 24. Cosmetic composition, characterized in that itcontains, in a cosmetically acceptable support, at least one compound asdefined according to any one of claims 1 to
 18. 25. Compositionaccording to claim 24, characterized in that the concentration of atleast one compound according to any one of claims 1 to 18 is between0.001 and 3% by weight relative to the total weight of the composition.26. Use of a cosmetic composition as defined according to either ofclaims 23 and 25, for body or hair hygiene.